DESCRIPTION (Applicant's Abstract): The long-range goal of the proposed studies is to understand the function of homeobox-containing genes in mammalian limb development. The applicant has devised two specific aims toward that end. The first aim will be to use gene targeting in mouse embryo- derived stem cells (ES cells) to generate mouse mutants with targeted disruptions in each of 11 homeobox- containing (Hox) genes of interest in three linkage groups (including hoxa-10, -11, -13; hoxc-10, -11, -12, -13; hoxd- 10, -11, -12, & -13). The limbs from each of these loss-of-function mutants will be examined for defects to define the zone of influence of each of the genes. The applicant anticipates that through systematic analyses of the phenotypes of all these mutants, some logic will emerge regarding the relationships between these genes and their role in limb patterning. The second aim is to determine how these genes interact in regulating limb development.Additional gene targeting and cross-breeding will be used to combine appropriate single mutations to generate double and triple mutants. The applicant will then analyze the phenotypic outcome of combining the mutations both within and across linkage groups. In addition, the influence exerted by mutation of one hox gene on the expression of another will be examined by introducing the lacZ reporter gene into the latter.